ABSTRACT The overall goal of this proposal is to understand the mechanism by which Rho GTPases, Rab GTPases, tethering agents, and SNAREs contribute to direct polarized trafficking and growth at the cell surface. Previous work from our laboratories and others has implicated members of the Rho/Cdc42 and Sro7/Tomosyn/Lgl protein families as factors that have important roles in both polarity and membrane trafficking to the cell surface in yeast and neurons. Spatial regulation of trafficking in yeast requires specific patterns of Rho/Cdc42 localization as well as tight regulation of vesicle tethering and fusion by the exocyst complex and Lgl/Sro7 protein. In this proposal, we will examine the mechanism by which Sro7 acts as a Rab-dependent tethering agent in exocytosis, and how gain-of-function mutants in the exocyst which mimic Rho GTPase activation of the exocyst complex, structurally change in order to upregulate its activity as a Rab-dependent tethering agent. Additionally, we will explore the hypothesis that a novel schizophrenia-linked protein with homology to an endocytic SNARE protein, acts to regulate exo/endocytic trafficking in the neuron.